CN1951950A - Helicid modifier and its preparation method and uses - Google Patents
Helicid modifier and its preparation method and uses Download PDFInfo
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- CN1951950A CN1951950A CN 200610048824 CN200610048824A CN1951950A CN 1951950 A CN1951950 A CN 1951950A CN 200610048824 CN200610048824 CN 200610048824 CN 200610048824 A CN200610048824 A CN 200610048824A CN 1951950 A CN1951950 A CN 1951950A
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Abstract
The invention discloses a new decorative of bean curd with structure formula (I), which is characterized by the following: adopting the decorative as active component of drug component; fitting for preparing sedative-hypnotic and antiphlogistic anodyne.
Description
Technical field: the present invention relates to novel Helicid modifier, its preparation method is the pharmaceutical composition of activeconstituents with such Helicid modifier, and they are in the preparation sedative hypnotic drug and the application in the preparation anti-inflammation analgesis medicament.
Background technology: helicidum (Helicid) is the effective constituent monomer glucosides (4-formylphenyl-β-allose) that extracts from the fruit of Proteaceae mountain Euphoria (HeliciaLour.) several plant, has the effect of calming soporific and relieving inflammation and relaxing pain.Any report that the sweet modifier of bean curd fruit is not arranged in the prior art.
Summary of the invention: the object of the present invention is to provide a class new have Helicid modifier of pharmaceutical use and preparation method thereof, further purpose provides the application of The compounds of this invention Helicid modifier in preparation sedative hypnotic drug and anti-inflammation analgesis medicament.
The present invention is based on following principle, the carboxaldehyde radicals of helicidum is active, such as with helicidum the allose hydroxyl synthetic fat soluble derivatives of company, then pass through hemato encephalic barrier easily, have better tranquilizing soporific and anti-inflammatory and analgesic effect, the present invention designs and has synthesized helicidum new decorative object (structure is seen formula I) for this reason, and by the synthetic helicidum new decorative object of helicidum, this new decorative object has multiple valuable medical actives such as tranquilizing soporific and relieving inflammation and relaxing pain.And developed the application in preparation sedative hypnotic drug and anti-inflammation analgesis medicament of this new decorative object.
Helicidum new decorative object of the present invention is represented with following structural formula (I):
Formula (I)
The helicidum new decorative object connects the group difference according to hydroxyl and mainly contains following three types:
1. helicidum alkane acylate: promptly hydroxyl is synthetic through acylations on the helicidum allose, comprises tetrem acidylate helicidum, four propionyl helicidums, four Butyrylation helicidums and four succinic acid half-ester helicidums.
2. helicidum etherate: promptly hydroxyl connects alkyl on the helicidum allose, comprises tetramethyl ether helicidum, tetrem ether helicidum.
3. helicidum aroylation thing: promptly hydroxyl is synthetic through aroylation on the helicidum allose, comprises four benzoyl helicidums, four benzyl formyl helicidums.
The compounds of this invention helicidum new decorative object is to be synthesized into by following method: get helicidum and be dissolved in the pyridine, add certain acid anhydrides ROR (R with formula I in consistent) or succinyl oxide (adopting DMAP to make catalyzer), in 60 ℃ of heating in water bath 3 hours, reaction product obtained the helicidum new decorative object through means of purification such as weak acid and weak base solution washing post crystallizations.
Compound helicidum new decorative object of the present invention can be used for preparing sedative hypnotic drug and anti-inflammation analgesis medicament.
When The compounds of this invention is used as medicine, can adds vehicle and directly use, or form compound preparation with other drug and use with suitable preparation.All the other are acceptable to humans and animals nontoxic and inert pharmaceutically acceptable carrier and/or vehicle on the pharmacology.Pharmaceutical carrier or vehicle are acceptable to the nontoxic and inert solid of humans and animals, semisolid and liquid diluent, filler and pharmaceutical preparation assistant agent on the pharmacology.Pharmaceutical composition of the present invention is used with the form of per weight dose.Medicine of the present invention can be through injection (quiet notes, intramuscular injection) and oral two kinds of form administrations.Usage quantity can be carried out one or many according to variations such as the type of route of administration, patient's age, body weight, the disease of being treated and severity and be used.Concerning the adult, 1～100mg every day is proper for dosage.
Embodiment: the following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Embodiment 1: the preparation of tetrem acidylate helicidum.
Getting the 200g helicidum is dissolved in the 200mL pyridine; add the 400mL diacetyl oxide; in 60 ℃ of heating in water bath 3 hours; reactant directly adds suitable quantity of water and separates out solid, will separate out solid and smash to pieces, successively adopt the 1000ml dilute hydrochloric acid (2%) and 1000ml yellow soda ash (5%) aqueous solution in the B suction filtration each 3 times; water flushing again; to wash back solid heating and be dissolved in 500ml 95% spirituous solution, through crystallization and repeatedly recrystallization obtain 283g tetrem acidylate helicidum, yield is 88.9%.
The structure appraising datum of tetrem acidylate helicidum:
UV spectrum (UV) is measured with the UV-210A instrument.Infrared spectra (IR) Bio-RadFTS-135 type spectrophotometric determination, the KBr compressing tablet.Optically-active JASCO-20 type polarimeter.Fusing point shows micro-MELTING POINT TESTER with the X-4 numeral.Mass spectrum (MS) is measured with Auto SPEC 3000 type mass spectrographs.Nuclear magnetic resonance spectrum (
1H NMR and
13C NMR) uses Bruker
The DRX-400 NMR spectrometer with superconducting magnet is measured, mark in TMS does, CDCl
3Make solvent.
Structural formula is suc as formula shown in (II):
Formula (II)
Molecular formula: C
21H
24O
11
Molecular weight: 452
Proterties: white crystals
Fusing point: 122-124 ℃
Optically-active: [α]
D 21-28.7 ° (c 0.61, CHCl
3)
UV(CHCl
3)：λ
max＝231，235，266。
IR(KBr)：ν
max＝2977，1748，1693，1606，1583，1513，1431，1370，1220，1172，1066，945，905，848，671，616cm
-1。
FAB-MS(+)：m/z＝453([M+H]
+，3)，331(100)，393(17)，271(2)，169(23)，145(2)，109(103)，81(3)。
1H-NMR(CDCl
3，400MHz)：δ
H 9.88(1H，s，CHO)，7.83(2H，d，J＝8.6Hz，H-3，5)，7.11(2H，d，J＝8.6Hz，H-2，6)，5.72(1H，m，H-3′)，5.46(1H，d，J＝8.0Hz，H-1′)，5.17(1H，dd，J＝8.0，2.9Hz，H-2′)，5.04(1H，dd，J＝9.6，2.6Hz，H-4′)，4.28-4.21(3H，m，H-5′，6′)，2.14，2.04，2.01，1.99(12H，s，4COCH
3)。
13C-NMR(CDCl
3，100MHz)：δ
c 190.8(s，CHO)，170.6，169.7，169.0，169.0(s，4
COCH
3)，161.4(C-1)，131.7(d，C-2，6)，131.6(s，C-4)，116.7(d，C-3，5)，96.2(d，C-1′)，70.6(d，C-5′)，68.5(d，C-2′)，68.2(d，C-3′)，65.9(d，C-4′)，62.1(t，C-6′)，20.7，20.6，20.5，20.5(q，4CO
CH
3)。
The preparation of 2: four succinic acid half-ester helicidums of embodiment.
Getting the 0.7g helicidum is dissolved in the 5mL pyridine, add 1g Succinic anhydried and 1.14g4-N, N-lutidine (DMAP), in 60 ℃ of heating in water bath 3 hours, reactant adds suitable quantity of water, uses chloroform extraction three times, and chloroform is partly passed through gel (Sephadex LH-20) chromatography, and (moving phase is chloroform: methyl alcohol=1: 1), obtain 1.42g four succinic acid half-ester helicidums, yield is 84.2%.
The structure appraising datum of four succinic acid half-ester helicidums:
Optically-active JASCO-20 type polarimeter.Mass spectrum (MS) is measured with Auto SPEC 3000 type mass spectrographs.Nuclear magnetic resonance spectrum (
1H NMR and
13C NMR) measures mark in TMS does, CD with Bruker DRX-400 NMR spectrometer with superconducting magnet
3OD makes solvent.
Structural formula is suc as formula shown in (III):
Formula (III)
Molecular formula: C
29H
32O
19
Molecular weight: 684
Proterties: clear wax shape
Optically-active: [α]
D 21-6.2 ° (c 0.91, CH
3OH)
FAB-MS (+): m/z=123 (aglycon fragment peak, [C
7H
6O
2+ H]
+, 100), 115 (7),, 109 (14), 101 (36), 98 (8), 81 (13), 69 (4).
1H-NMR(CD
3OD，400MHz)：δ
H 9.66(1H，s，CHO)，7.66(2H，d，J＝8.0 Hz，H-3，5)，6.98(2H，d，J＝8.0Hz，H-2，6)，5.57(1H，m，H-3′)，5.37(1H，d，J＝7.9Hz，H-1′)，4.93(1H，dd，J＝7.6，2.6Hz，H-2′)，4.85(1H，m，H-4′)，4.15-4.07(3H，m，H-5′，6′)，2.53-2.37(16H，m，4COCH
2CH
2COOH)。
13C-NMR(CD
3OD，100MHz)：δ
c 192.2(s，CHO)，175.1，172.9，172.2，171.6(s，4
COCH
3)，162.1(C-1)，132.4(d，C-2，6)，132.0(s，C-4)，117.3(d，C-3，5)，96.6(d，C-1′)，71.1(d，C-5′)，69.5(d，C-2′)，68.5(d，C-3′)，66.8(d，C-4′)，63.1(t，C-6′)，29.6-28.8(t，4COCH
2CH
2CH
3)。
Following example of formulations is that the method by embodiment 1 makes the helicidum new decorative object earlier, pulvis, pelletizing press sheet, the capsule making injection liquid, powder injection, oral liquid routinely and add vehicle.
[example of formulations 1] tablet
Prepare tablet according to methods known in the art, every contains following compositions:
Formula (I) compound 50mg
Lactose 70mg
Magnesium Stearate 3mg
Polyvinylpyrrolidone 7mg
Add up to 130mg
If desired, tablet can carry out the film coating with Vltra tears, talcum and tinting material.
[example of formulations 2] capsule
Prepare capsule according to methods known in the art, contain following compositions in each capsule:
Formula (I) compound 50mg
Lactose 70mg
W-Gum 25mg
Magnesium Stearate 1mg
Polyvinylpyrrolidone 4mg
Add up to 150mg
[example of formulations 3] injection
Method by embodiment 1 makes formula of the present invention (I) compound earlier, prepares injection by methods known in the art, adds the injection water, smart filter, and injection liquid is made in the embedding sterilization.
Following test example can further specify the beneficial effect of Helicid modifier of the present invention and pharmaceutical composition thereof, and these test examples have comprised pharmacodynamics test of the present invention and acute toxicity test etc.
Test example 1: the pharmacological action of tetrem acidylate helicidum in the The compounds of this invention helicidum new decorative object.
The experiment of tetrem acidylate helicidum sedative-hypnotic effect
(1) experimental technique
The method that the spontaneous activity in mice number of times is measured, the sub-threshold dose vetanarcol are worked in coordination with hypnosis test, the threshold dose vetanarcol determination test length of one's sleep in the employing herbal pharmacology experimental methodology (these methods are seen [1] Li Yikui etc. the herbal pharmacology experimental methodology. and Shanghai science tech publishing house, 1991:330; [2] Li Yikui etc. the herbal pharmacology experimental methodology. Shanghai science tech publishing house, 1991:334 and [3] Qi Chen etc. the description in herbal pharmacology research methodology .1993:113～114) test, all adopt and repeatedly irritate stomach and two kinds of administering modes of single intraperitoneal injection.Experiment is provided with the solvent contrast, with the positive contrast of diazepam.
Laboratory animal is adopted SPF level ICR mouse, 3～4 ages in week, and male and female half and half, body weight 18～22g is provided by unming Medical College's Experimental Animal Center.Tried thing (tetrem acidylate helicidum: DA55) by the invention provides.
(2) experimental result
Experimental result see Table 1-6 (compare with control group:
*P＜0.05,
*P＜0.01).
Many gastric infusions of table 1 are to the influence of spontaneous activity in mice
The administration of table 2 single intraperitoneal injection is to the influence of spontaneous activity in mice
Many gastric infusions of table 3 are to the influence of sub-threshold dose vetanarcol mice sleep rate
| Group | Dosage (mg/kg) | Number of animals (only) | Sleeping number of animals (only) | Sleeping rate (%) |
| Solvent contrast diazepam DA55 | - 2 400 100 | 12 10 10 10 | 2 9 9 9 | 17 90 ** 90 ** 90 ** |
Table 4 single intraperitoneal injection is to the influence of sub-threshold dose vetanarcol mice sleep rate
| Group | Dosage (mg/kg) | Number of animals (only) | Sleeping number of animals (only) | Sleeping rate (%) |
| Solvent contrast diazepam DA55 | - 2 400 200 | 10 10 10 10 | 1 9 10 9 | 10 90 ** 100 ** 90 ** |
Many gastric infusions of table 5 are to the influence of threshold dose vetanarcol mouse sleep time
Table 6 single intraperitoneal injection is to the influence of threshold dose vetanarcol mouse sleep time
DA55 with the continuous gastric infusion of the dosage of 400mg/kg 3 days or intraperitoneal injection once can obviously suppress the spontaneous activity of mouse; DA55 with 400,200, the dosage continuous irrigation stomach 3 days of 100mg/kg or intraperitoneal injection once, can improve the sleeping rate of sub-threshold dose vetanarcol mouse in various degree, act as significantly with high dose group; DA55 with the continuous gastric infusion of the dosage of 400mg/kg 3 days or DA55 with 400,200, the 100mg/kg intraperitoneal injection once, all can obviously prolong the sleep time of threshold dose vetanarcol mouse, DA55 three dosage group intraperitoneal injections can also obviously shorten the sleep latent period of mouse.Above result shows that DA55 has tangible sedative-hypnotic effect.
Test example 2: the experiment of tetrem acidylate helicidum anti-inflammatory and analgesic effect
(1) experimental technique
Acetic acid in the employing herbal pharmacology experimental methodology causes the test of mouse writhing pain, hot plate causes the method that mouse pain is tested, mice caused by dimethylbenzene xylene auricle clock expands test (example 1 is identical with testing) and tests, and all adopts and repeatedly irritates stomach and two kinds of administering modes of single intraperitoneal injection.Experiment is provided with the solvent contrast, with the positive contrast of acetylsalicylic acid.
Laboratory animal is adopted SPF level ICR mouse, 3～4 ages in week, and male and female half and half, body weight 18～22g is provided by unming Medical College's Experimental Animal Center.Tried thing (tetrem acidylate helicidum: DA55) by the invention provides.
(2) experimental result
Experimental result sees Table 7-11 and compares with control group:
*P＜0.05,
*P＜0.01).
7 days Dichlorodiphenyl Acetates of table 7 DA55 successive administration cause the influence of mouse writhing pain
| Group | Dosage (mg/kg) | Number of animals (only) | Turn round body number of times (X ± SD, inferior) | Inhibiting rate (%) |
| Solvent contrast acetylsalicylic acid DA55 | - 200 200 50 | 12 12 12 12 | 33.8±12.4 7.4±7.7 ** 13.5±13.5 ** 18.5±18.7 * | - 78.10 60.00 45.27 |
4 days Dichlorodiphenyl Acetate induced mice of table 8 DA55 successive administration are turned round the influence of body pain
| Group | Dosage (mg/kg) | Number of animals (only) | Turn round body number of times (X ± SD, only) | Inhibiting rate (%) |
| Solvent contrast acetylsalicylic acid DA55 | - 200 50 10 | 10 10 10 10 | 30.3 ±12.2 10.4±10.9 ** 19.2±17.4 * 11.9±15.0 ** | - 65.67 35.64 60.73 |
Table 9 DA55 single-dose causes the influence of painful mouse to hot plate
| Group | Dosage (mg/kg) | Number of animals (only) | Before the administration (X ± SD, second) | Different time threshold of pain after the administration (X ± SD, second) | |
| 30min | 60min | ||||
| Solvent contrast acetylsalicylic acid DA55 | - 200 100 | 10 10 10 | 17.4±5.7 18.8±3.1 17.8±5.2 | 17.6±7.1 27.2±18.7 23.3±17.6 | 16.7±5.8 21.2±15.5 19.9±8.6 |
Table 10 DA55 p-Xylol causes the influence of mice auricle swelling degree
Table 11 DA55 successive administration is to causing the influence of mice auricle swelling degree
| Group | Dosage (mg/kg) | Number of animals (only) | Auricle swelling degree (X ± SD, mg) | Inhibiting rate (%) |
| Solvent contrast acetylsalicylic acid DA55 | - 200 200 100 50 10 | 12 12 12 12 12 12 | 12.7±5.1 4.9±4.6 ** 1.1±0.9 ** 7.2±4.3 * 7.5±4.9 * 8.5±2.9 * | - 61.42 91.34 43.31 40.94 33.07 |
DA55 with 200, the continuous gastric infusion of dosage of 50mg/kg 7 days, with 50,10mg/kg successive administration 4 days, the Dichlorodiphenyl Acetate induced mice is turned round body pain remarkable restraining effect; With gastric infusion of dosage of 100mg/kg, the threshold of pain that hot plate is caused painful mouse has certain prolongation trend; The continuous gastric infusion of the DA55 of 5mg/kg 3 days, p-Xylol induced mice auricle edema has remarkable restraining effect, and with 200,100,50, the dosage successive administration of 10mg/kg 8 days, p-Xylol induced mice auricle edema has remarkable restraining effect.The result shows that DA55 has clear and definite analgesia and anti-inflammatory action.
Test example 3. tetrem acidylate helicidum acute toxicity tests
(1) experimental technique
Adopting mouse once to irritate the stomach maximum dosage-feeding measures.
Laboratory animal is adopted SPF level ICR mouse, in 3～4 ages in week, is provided by unming Medical College's Experimental Animal Center.Test is carried out at the IVC Animal Lab..Tried thing (tetrem acidylate helicidum: DA55) by the invention provides.Take by weighing sample 15.0020g in mortar, add and move in the graduated cylinder after a little 0.5%CMC-Na of people grinds, clean mortar 2 times with a small amount of solvent, transfer total volume to 33ml, with the Stainless Steel cutter stir concentration be that the oyster white mashed prod of 0.45g/ml is the peak concentration of this test.
The mouse fasting be can't help water after 5 hours, and choosing body weight is 40 of 18～21g persons, and male and female half and half are divided into 2 groups at random by sex and body weight: the blank group; The DA55 group; Every group 20.Administration group mouse is once irritated stomach by the volume of 40ml/kg body weight and gives tetrem acidylate helicidum mashed prod, and the blank group gives the 0.5%CMC-Na with volume.
(2) experimental result
Except that female 3 of tetrem acidylate helicidum group, male 4 animals about 20min activity after administration have the minimizing slightly, all the other animal appearance, behavioral activity, the mental status, appetite, stool and urine, fur, the colour of skin and breathing etc. there is no the overt toxicity reaction and take place.Observed 14 days continuously, all healthy survival of animal, body weight obviously increases, and two groups are not relatively had significant difference, the results are shown in Table for 12 observation periods extremely to dissect viscera tissues such as animal, the visual inspection heart, liver, spleen, lung, kidney everywhere, also show no obvious abnormalities.
Table 12 tetrem acidylate helicidum is through mouse stomach approach acute toxicity test body weight result
| Group | Sex | Before the administration | Different time after the administration (X ± SD, g) | ||||
| 3d | 5d | 7d | 9d | 14d | |||
| Control group DA55 | ♀ ♂ ♀ ♂ | 19.1±0.8 20.6±0.6 19.6±1.2 20.64±0.5 | 21.1±1.0 22.84±0.9 20.54±0.9 23.0±0.3 | 22.7±1.6 25.4±1.2 21.3±1.2 29.5+2.9 | 23.4±1.9 26.6±1.9 22.5±1.3 26.4±1.3 | 23.5±2.4 28.5±2.4 22.4±1.1 27.5±1.6 | 24.54-1.6 29.54-2.9 23.1±2.0 29.8-4-2.1 |
Toxicity prerun shows that the oral DA55 of mouse because of concentration and volume reason, can't measure LD
50So, reflect the acute toxicity situation of this sample with the maximum dosage-feeding of once irritating stomach.Mouse is once irritated stomach with the maximum volume of the peak concentration of 0.45g/ml, 40ml/kg and gives DA-55, except that nearly 1/3 animal activity amount has the minimizing slightly, does not see that other overt toxicity reaction takes place; The mouse once maximum dosage-feeding of oral DA-55 is 18.0g/kg, and its maximum tolerated dose must be greater than 18.0g/kg.
Claims (6)
1, following structural formula (I) Helicid modifier
R＝COCH
3
R＝COCH
2CH
3
R＝COCH
2CH
2CH
3
R＝COCH
2CH
2COOH
R＝CH
3
R＝CH
2CH
3
R＝COAr
R＝COCH
2Ar
(I)。
2, the method for preparing claim 1 Helicid modifier, getting helicidum is dissolved in the pyridine, add certain acid anhydrides ROR, consistent or the succinyl oxide of R among R and the formula I wherein, adopt DMAP to make catalyzer, in 60 ℃ of heating in water bath 3 hours, reaction product got Helicid modifier through weak acid, weak base aqueous solution washing post crystallization purifying.
3, the pharmaceutical composition that is used for tranquilizing soporific wherein contains claim 1 Helicid modifier and/or the pharmaceutically acceptable carrier for the treatment of significant quantity.
4, the pharmaceutical composition that is used for relieving inflammation and relaxing pain wherein contains claim 1 Helicid modifier and/or the pharmaceutically acceptable carrier for the treatment of significant quantity.
5, the application of claim 1 Helicid modifier in the preparation sedative hypnotic drug.
6, the application of claim 1 Helicid modifier in the preparation anti-inflammation analgesis medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100488241A CN100413877C (en) | 2006-11-17 | 2006-11-17 | Helicid modifier and its preparation method and uses |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100488241A CN100413877C (en) | 2006-11-17 | 2006-11-17 | Helicid modifier and its preparation method and uses |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1951950A true CN1951950A (en) | 2007-04-25 |
| CN100413877C CN100413877C (en) | 2008-08-27 |
Family
ID=38058522
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101029065B (en) * | 2007-04-11 | 2010-05-19 | 昆明贝克诺顿制药有限公司 | Bean-curd pectin analogue and its use in medicine for preventing depression |
| CN101810632A (en) * | 2010-03-16 | 2010-08-25 | 云南大学 | Purpose of 4-cyan-beta-D-glucoside for curing tristimania |
| CN101933933A (en) * | 2010-03-16 | 2011-01-05 | 云南大学 | Application of 2-fluoro-beta-D-glucoside in treating depression |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000007693A (en) * | 1998-06-26 | 2000-01-11 | Lederle Japan Ltd | Chlorin derivative |
| CN1634089A (en) * | 2003-12-29 | 2005-07-06 | 昆明贝克诺顿制药有限公司 | Application of p-benzaldehyde-O-beta-D-allopyranoside in treating neuropathic pain |
-
2006
- 2006-11-17 CN CNB2006100488241A patent/CN100413877C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101029065B (en) * | 2007-04-11 | 2010-05-19 | 昆明贝克诺顿制药有限公司 | Bean-curd pectin analogue and its use in medicine for preventing depression |
| CN101810632A (en) * | 2010-03-16 | 2010-08-25 | 云南大学 | Purpose of 4-cyan-beta-D-glucoside for curing tristimania |
| CN101933933A (en) * | 2010-03-16 | 2011-01-05 | 云南大学 | Application of 2-fluoro-beta-D-glucoside in treating depression |
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|---|---|
| CN100413877C (en) | 2008-08-27 |
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